Reprogramming primordial germ cells into pluripotent stem cells.
BACKGROUND
Specification of primordial germ cells (PGCs) results in the conversion of pluripotent epiblast cells into monopotent germ cell lineage. Blimp1/Prmt5 complex plays a critical role in the specification and maintenance of the early germ cell lineage. However, PGCs can be induced to dedifferentiate back to a pluripotent state as embryonic germ (EG) cells when exposed to exogenous signaling molecules, FGF-2, LIF and SCF.


RESULTS
Here we show that Trichostatin A (TSA), an inhibitor of histone deacetylases, is a highly potent agent that can replace FGF-2 to induce dedifferentiation of PGCs into EG cells. A key early event during dedifferentiation of PGCs in response to FGF-2 or TSA is the down-regulation of Blimp1, which reverses and apparently relieves the cell fate restriction imposed by it. Notably, the targets of Blimp1, which include c-Myc and Klf-4, which represent two of the key factors known to promote reprogramming of somatic cells to pluripotent state, are up-regulated. We also found early activation of the LIF/Stat-3 signaling pathway with the translocation of Stat-3 into the nucleus. By contrast, while Prmt5 is retained in EG cells, it translocates from the nucleus to the cytoplasm where it probably has an independent role in regulating pluripotency.


CONCLUSIONS
We propose that dedifferentiation of PGCs into EG cells may provide significant mechanistic insights on early events associated with reprogramming of committed cells to a pluripotent state.
Durcova-Hills
Gabriela
G
Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Cambridge, United Kingdom. gd225@cam ac.uk
Tang
Fuchou
F
Doody
Gina
G
Tooze
Reuben
R
Surani
M Azim
MA
D000818:Animals; D054337:Cell Dedifferentiation / Q000235:genetics / Q000502:physiology*; D019070:Cell Lineage / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental; D016259:Genes, myc; D005854:Germ Cells / Q000378:metabolism / Q000502:physiology*; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D008297:Male; D051379:Mice; D008954:Models, Biological; D039904:Pluripotent Stem Cells / Q000378:metabolism / Q000502:physiology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011247:Pregnancy; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; C513258:Prdm1 protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1